This invention relates to methods of identifying universal tumor associated antigens, and use of such antigens in the prevention, treatment, and diagnosis of cancer.
The paucity of clinically significant anti-tumor immune responses in cancer patients has long suggested that antigen-specific immunotherapy would not play a significant role in cancer treatment. However, pioneering studies in the early 1990s, using tumor-specific cytotoxic T lymphocytes (CTLs) from cancer patients, showed the existence of human tumor associated antigens (TAAs), suggesting that such antigens could be used to stimulate therapeutic anti-tumor immune responses in patients. Although these studies primarily focused on melanoma, TAAs have been subsequently characterized in several other malignancies, raising the hypothesis that most, if not all, tumors express antigens that can be used to induce CTL-mediated tumor destruction. Consequently, exciting clinical efforts are now underway to target these TAAs in strategies such as vaccination and adoptive T cell therapy to generate effective anti-tumor CTL responses in patients.
Unfortunately, most TAAs described thus far are expressed in only one or a few tumor types, and not all patients with a given tumor type express the associated TAA. As a result, progress in the field of cancer immunotherapy has been relatively slow, because it has not been possible to develop widely useful TAA-specific immunotherapeutic strategies. Not only has it been necessary to tailor such therapies to individual types of malignancies, in some cases (such as the immunoglobulin idiotypic antigen in B cell malignancies), it has been necessary to tailor these therapies to individual patients.
More than 85% of human cancers display telomerase activity (Kim et al., Science 266:2011-2015, 1994). Telomerase is a ribonucleoprotein complex that maintains the telomeric ends of linear chromosomes, thus protecting them from degradation and end-to-end fusion. The human telomerase complex contains a reverse transcriptase, known as hTERT, and an RNA component that is used as a template for telomere synthesis by hTERT. The hTERT subunit is the rate-limiting component of the complex, and its expression correlates best with telomerase activity. Most human cells do not express hTERT or display telomerase activity, and therefore lose telomeric DNA with each cell division. In contrast, more than 85% of human tumors express hTERT, exhibit strong telomerase activity, and maintain the length of their telomeres, suggesting that the activation of telomerase plays an important role in the development of human cancers.